The autoimmune diseases are due to a dysfunction of the immune system which recognizes in an inappropriate way some self components leading to abnormal immunization responses. The body “is attacked” by its own immune system. Today the list of the autoimmune diseases is exhaustive and understands inter alia: inflammatory bowel disease (IBD) such as Crohn's disease and hemorrhagic rectocolitis; multiple sclerosis; psoriatic arthritis; Basedow's disease; rheumatoid arthritis; disseminated erythematous lupus; insulino-dependent diabetes, spondylarthritis, etc. Among the autoimmune diseases which represent an urgent medical need, we will describe in a descriptive but nonrestrictive way: Crohn's disease, hemorrhagic rectocolitis, multiple sclerosis and psoriasis. In most autoimmune diseases such as Crohn's disease, psoriatic arthritis, etc, some cytokines as TNF-α induce an attack of healthy tissue and produce various lesions characteristic of each pathology.
Inflammatory bowel diseases (IBD) are diseases characterized by a chronic inflammation which affects the intestines. The physiopathological mechanism common to the IBD is the inflammation of the intestinal mucous membrane. This inflammation is made by an activation of the intestinal immune system which is triggered by both genetic traits and environmental factors. This IBD group includes two great chronic and recurring diseases, which evolve by crisis and which tend to carry on all the life:                Crohn's disease which can affect the whole digestive tract almost from the mouth to the anus and preferentially the final part of small intestine and the beginning of colon. The diagnosis is based on chronic diarrhea, abdominal pain, perianal fistulae or abscesses, slimming and fever. The continuation of the inflammation in Crohn's disease and in ulcerative colitis can be checked partly by an increased secretion of pro-inflammatory cytokines (Reinecker H C et al, Clin. Exp. Immunol 1993; 94: 174-181). According to the same publication, dosage of the pro-inflammatory TNF-α, IL-1-β and IL-6 cytokines from colon biopsy represents a sensitive method to monitor the severity of mucosal inflammation in patients affected by IBD;        hemorrhagic rectocolitis which is located only on rectum and colon.        
Against the severe forms of IBD, various treatments allow the patients today to treat the symptomatic crisis and, to a lesser extent, to space them by using anti-inflammatory drugs; corticoids; immunosuppressive agents; biotherapies and surgery. Among anti-inflammatory drugs treatments, we can quote salicylated derivatives which induce less toxicity. Mesalazin is, according to current practice, the treatment which is administered at the beginning of the first inflammatory crisis. Then are used more powerful, but also more toxic anti-inflammatory drugs, such as cortisone. When these treatments appear ineffective; there is still the possibility to use a more recent therapeutic, such for Crohn's disease: a new treatment called Remicade™ which corresponds to a monoclonal antibody against TNF-α. This is a highly targeted drug but also very expensive which can, for example, treat crisis resistant to the treatment by cortisone, and maintain Crohn's disease in remission. As maintenance treatment, to prevent that the patient does not relapse, are used salicylated and immunosuppressive agents which depress immunity; the latter being over expressed in patients affected by one of the above diseases. Unfortunately, it is often necessary to resort to surgery in patients affected by one of these diseases: after eight to ten years of evolution, more than one patient out of two affected by Crohn's disease will be operated, firstly because it often appears shortenings of the intestine; sometimes, in approximately 20% of the cases, also abscesses can be located around the anus area. Among patients affected by hemorrhagic rectocolitis who are resistant to the treatment, there is then the resort to the surgery which consists in removing colon and rectum; this being a relatively heavy intervention. However, in subjects affected by Crohn's disease, surgery treats only the complications and does not prevent the disease from reappearing after the patient's operation.
The rheumatoid arthritis (RA) is an auto-immune disease of unknown precise origin; it is the most frequent cause of chronic polyarthritis. It represents the inflammatory type of rheumatism the most found in the adult. Its prevalence is evaluated between 0.3 and 0.8% according to the countries. It is characterized by an often bilateral and symmetrical articular attack, evolving by crisis to the deformation and the destruction of the attacked articulations. The disease generally starts by polyarthritis, i.e. inflammation of 4 or more articulations, characterized by scheduled inflammatory pain (wake up during the night, more than 30 minutes stretching during the morning), an articular stiffness, and a swelling called synovitis. Generally, the evolution, which lasts over several decades, is done by crisis, spaced by remissions of unpredicted rhythm and duration. During the crisis, most articulations are swollen and painful, and are associated with general signs (febricula, asthenia) and frequently with a biological inflammatory syndrome. The follow-up of the activity of the disease can be done using various scores. More used in clinical practice is the DAS 28, calculated starting from 4 parameters: the articular index (many painful articulations—except feet, ankles and hips not entered), the synovial index (many swollen articulations—except feet, ankles and hips), activity of the disease evaluated on a scale from 0 to 100 by the patient, and the sedimentation test. The symptomatic treatment can comprise the mere rest at the time of the crisis, the classic antalgic treatments, the non-steroidal anti-inflammatory drugs, the low dose corticosteroids, lower than 10 mg/day to restrict their side effects. Concerning the disease-modifying drugs and according to the severity of the disease, there exists currently a series of molecules which can be used such as in particular methotrexate; some immunosuppressors such as azathioprine or cyclosporine; anti-αTNF; CTLA4 inhibitor or anti-CD20. However, some of these molecules must be used with caution because of important side effects that they cause, or are not sufficiently effective in some patients, or then must be taken in association.
Multiple sclerosis (MS) is an inflammatory disease affecting the central nervous system. It involves, in particular, an inflammatory demyelination, a myelin destruction in the white substance of brain and marrow. Old lesions are the place when astrocytes proffer; characterizing sclerosis of the nervous tissue. These demyelinating lesions have a singular distribution and topography: not diffused but in plaques. Multiple forms that characterize the pathology renders it difficult for the family circle to understand, and is complex to diagnose it for the medical community. Current treatments aim at limiting frequency and extent of inflammatory crisis. They comprise two parts: a crisis treatment and a basic treatment. As crisis treatment, corticosteroids are sometimes prescribed as relay during approximately 3 weeks by oral route, associated with preventive measures in regard to the side effects of corticosteroids. As basic treatment, beta interferon and glatiramer acetate (copolymer of several amino-acids) are generally prescribed. In the severe forms, immunosuppressive agents such as mitoxantrone can be prescribed. Antibodies such as natalizumab (antibody against the a chain integrin of leucocytes) and Remicade™ (monoclonal anti-TNF-α) are also prescribed.
Psoriasis is a skin disease for which origin, partly genetic, is poorly known. This dermatological pathology affects between 1 and 3% of the population, indifferently women or men. There are several psoriasis types: psoriasis vulgaris, psoriasis eruptiva, psoriasis erythrodermic, psoriasis pustular, psoriatic arthritis. In its benign form, the psoriasis is limited to scalp, nails, knees, elbows, feet, hands and sometimes genitals. In the serious cases, it extends up to the whole body. This chronic dermatosis evolves in a very individual way, with eruptions, but also remissions during which the lesions disappear. Then, it is said that the psoriasis “is whitened”. The respite is of duration very variable and the remission often incomplete. To date, no curative treatment allowing to recover completely from psoriasis is known; however it is possible to restrain psoriasis; to decrease the lesions extent and to improve patient's life. There are various types of treatment:                a topical treatment for the non-severe form which consists in applying a cream containing corticosteroids, calcipotriene or tazarotene to the psoriasis area. These treatments have a favorable effect on psoriasis; unfortunately the plaques often reappear when the treatment stops. The last treatment generates also a form of desensitization, which obliges to increase doses with time. Moreover, the effect is not only topical if these pomades are applied to expanded area. This treatment form should thus be limited to acute or highly unaesthetic forms, during a short period and on a limited area;        a phototherapy treatment. The solar exposure has generally a favorable influence on the psoriasis. However, in 10% of the cases, this exposure will be harmful. Then, the subject will have to avoid sun, or at least to avoid being directly exposed to its rays;        a systemic treatment. For the most severe forms of psoriasis, the practitioner can prescribe a treatment to be administered orally or by injection. In this case, methotrexate, cyclosporine or anti-α TNF antibodies can be used. These treatments are called systemic because the drugs are intended to be disseminated in all the body. Often, they cause side effects, sometimes serious.        
From these examples, it results that currently available treatments to cure autoimmune diseases are of limited number and appear sometimes very heavy and ineffective. This explains the importance of the research in this field. Several pharmaceutical laboratories and Universities develop drugs or treatments in the autoimmune diseases. We can quote as example, purine-containing treatments (FR2851248A and WO 96/18397A); anti-cytokine or anti-receptor antibodies (US 2003232009A, WO 06/121852, WO 06/092530, EP 1593393A and WO 07/009,065); vaccines or auto-antigens (WO 01/74375, EP 1621208A, WO 07/044,394), etc. These therapeutic molecules are still in basic research or clinical studies and it is difficult now to evaluate their efficiency in man.
The Applicant was interested in a thymulin analogue peptide active on the immune system and in the treatment of autoimmune diseases. It is known since the end of the 1950's that thymus plays a central role in the differentiation of T lymphocytes, which are responsible in particular of graft rejection and of the defense against viruses and certain bacteria. The hormone secreted by the thymus was then identified as a 9 amino-acids peptide: the thymuline (Bach, Pleau et al Immunol letters, 1979; 1: 179-182; Amor et al, Annals of the Rheumatic Disease 1987: 46: 549-554). Thymulin properties on the immune system were proved to be zinc-dependant. Indeed, zinc associated with peptide confers on this one a tetrahedral conformation which corresponds to the active form of the molecule. In the absence of zinc, thymulin has no more activity on immune system.
Thymulin analogue peptides of this invention were already described for the treatment of inflammatory and neurogenic pain (WO 03/030927); Saade et al., Neuroscience, 2003; 119 (1): 155-65, and Safieh-Garabedian et al., Br J. Pharmacol. 2002 July; 136 (6): 947-55. In the last publication, it is reported that peptide PAT confers analgesic and anti-inflammatory effects, from a series of experiments carried out in rats by endotoxin intraplantar (i.p1) and intraperitoneal (i.p) injections. Cytokines dosages were carried out on skin and liver tissue sampling. It is important to specify that these authors were not interested by intestinal inflammatory pain, or by the pain from rheumatoid arthritis. Moreover, the model used in the latter application can by no means be regarded as a model to study autoimmune and inflammatory diseases such as IBD (Crohn's disease, hemorrhagic rectocolitis) or rheumatoid arthritis. Indeed, in this study, capsaicin model was used as visceral pain model; it is a molecule which causes burn and pain feelings. It is important to specify that it acts on the sensory neurons level but not on inflammation itself. In an example, capsaicin is injected in rats which beforehand received or not PAT peptide; and nociception scores (painful perception) caused by capsaicin are quoted. Firstly, due to its model of action, capsaicin model is not pertinent in the investigation of autoimmune diseases such as IBD. Moreover, patent application WO 03/030927 does not refer specifically to autoimmune diseases such as IBD of which Crohn's disease or hemorrhagic rectocolitis.
The Applicant was interested by determining whether the PAT nonapeptide, for which harmlessness was established, can be regarded as a new drug to treat autoimmune diseases such as IBD, rheumatoid arthritis, multiple sclerosis or psoriasis.